Ion channels are a component of multiprotein scaffolds regulated by molecular protein-protein interactions to control electrical excitability of neurons and provide proper subcellular adjacencies to downstream cell signaling machinery. The work in this proposal will focus upon non-traditional roles of a voltage-gated ion channel (Kv1.3) predominantly expressed in mitral cell neurons of the olfactory bulb to understand the contribution of voltage-gated activity to olfactory coding. The recently uncovered, multifarious role for K channels - including energy homeostasis, axon targeting, and development of neuronal cytoarchitecture - is poorly understood. A multidisciplinary approach using transgenic mouse models (odorant receptor-tagged mice, Kv1.3-null mice, YFP mitral cell mice, and MC4R-null mice) to study Kv1.3 activity is proposed incorporating the METHODS of olfactory bulb electrophysiology, protein biochemistry, intranasal hormone/drug delivery, olfactory discrimination (behavior), systems physiology, and anatomical analysis of olfactory circuitry as a means for determining the mechanistic details and global physiological effects of neuromodulation of voltage-gated activity in the olfactory bulb. The SPECIFIC AIMS of this proposal are based on three HYPOTHESES: 1. Interactions with signaling proteins in the insulin receptor kinase/phosphatase cascade regulate Kv1.3 ion channel activity. 2. Voltage-gated activity from Kv1.3 ion channels modulates olfactory bulb mitral cell activity and olfactory acuity. 3. Gene-targeted deletions of Kv1.3 channel protein and the melanocortin 4 receptor will provide mechanistic details of how this potassium channel regulates energy homeostasis that modulates olfactory sensory ability via glucose utilization. The broad, long-term OBJECTIVE of this research is to elucidate how neuromodulation of voltage-gated ion channel activity can give rise to diverse functions in the olfactory system such as long-term plastic changes in synaptic efficacy, links to energy metabolism, or to fine tune the expression of odorant receptors and their central targets. Understanding the general principles of how ion channels are regulated by well defined molecules enriched in the olfactory system and involved in metabolic disorders (diabetes) and neurodegenerative diseases (Alzheimer's) and why gene-targeted deletion of Kv1.3 increases olfactory ability and induces resistance to weight gain, holds great translational promise as a target for increasing odor discrimination or lessening imbalance in energy homeostasis (obesity). PUBLIC HEALTH RELEVANCE: Sixty-five percent of Americans are overweight; unwanted weight gain induces an increased workload on the heart and circulation, increases insulin resistance, and precipitates type II Diabetes. This proposal is designed to elucidate the basic cellular mechanisms of how ion channels expressed in the olfactory bulb are involved in body weight and energy metabolism; is there a link between olfactory ability and obesity?